This project will utilize highly developed libraries of antibody probes to neurofilament proteins and to cytoskeletal enzymes which modulate neurofilament proteins (i.e., calcium-activated neutral protease and calcium-activated transglutaminase) in order to characterize and compare the changes in the neuronal cytoskeleton which occur during maturation and aging of the neuron in experimental pathological and dysfunctional states and in neurodegenerative diseases such as pathological and dysfunctional states and in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Attention will be directed at the alterations of cytoskeletal proteins which may account for the accumulations of neurofilaments and/or their immunoreactive products in pathological and disease states. Mechanisms of change will be sought by examining the reactive changes in neurofilament proteins and the associated cytoskeletal enzymes in neurons which have been injured experimentally by axonal transection. Immunohistochemical and immunobiochemical methods will be used to assess the distributions of the different cytoskeletal proteins, their localization within the neuron as well as their varying amounts and forms within the tissues. The Program Project will apply concepts and methods from basic neurobiology to elucidate pathological and disease states of the neuron. It is hoped that these efforts will provide new insights and understandings on the nature of the neuronal cytoskeleton, its alteration during development and aging and its role in determining the manifestations of neuronal dysfunction and disease.